Longitudinal Outcomes of Anti-TNF Therapy in the Treatment of Inflammatory Bowel Disease

Introduction: Tumor necrosis factor α inhibitors (TNFi) are used for the long-term management of inflammatory bowel disease (IBD). Short to medium-term complications of TNFi include increased risks of infection, malignancy, immunogenicity, and hematologic and metabolic disorders. Despite their routine use, data concerning their safety beyond 5 years is limited. Thus, the aim of this study is to compare adverse events (AEs) in patients in clinical remission for at least 6 months who are on TNFi maintenance therapy for less than or greater than 5 years. Methods: This retrospective study included IBD patients on stable TNFi maintenance regimens defined as no change, escalation, or discontinuation in TNFi therapy for at least 6 months, and a normal C-reactive protein thereafter. Patients were divided into groups of less than (short-term) or greater than (long-term) 5 years on stable TNFi therapy. The primary outcome was time to any AE. Secondary outcomes analyzed AE categories (infection, malignancy, dermatologic, hematologic, metabolic, respiratory, hepatic, gastrointestinal, renal, neurologic, cardiovascular, pancreatic, musculoskeletal, endocrine, reproductive, infusion reaction, IBD related surgery). Time to an AE was examined by Kaplan-Meier failure estimates for each group from commencement of stable TNFi therapy (> 6 months) until a change in TNFi therapy or the date of the patient’s last visit, if there was no change in therapy. Multivariable Cox proportional hazards models adjusting for patient demographics, disease characteristics, and concomitant therapies were used to determine the relative hazard ratio (HR) of an AE occurring between groups. Results: There were 485 patients (304 short-term and 181 long-term patients) representing 1,232 person-years of time at risk. AEs occurred in 15% and 13% of the short and long-term groups, respectively. The most frequent AEs in the short-term and long-term groups were dermatologic (38% vs 30%), infection (11% vs 13%) and malignancy (7% vs 17%). We found a significantly lower risk of any AE (HR: 0.385; 95% CI: 0.204-0.726) and any dermatologic AE (HR: 0.105; 95% CI: 0.025-0.435) in the long-term group (Figure 1). The adjusted risk for other AEs were the same between groups. Conclusion: Patients on stable TNFi therapy for > 5 years exhibit a lower risk of overall and dermatological AEs, with no significant difference in the risk of other AE types, compared to those on therapy for < 5 years, indicating that the long-term use of TNFi appears safe (Table 1).Figure 1.: Kaplan-Meier time to any adverse event between those on greater than and those on less than 5 years of stable tumor necrosis factor inhibitor biologic therapy. Table 1. - Patient and disease baseline characteristics between those with stable disease on less than (short-term) and greater than 5 years (long-term) of TNFi biologic therapy Short-term (n = 166) Long-term (n = 163) P-value Short-term (n = 166) Long-term (n = 163) P-value TNFi duration (years) 2.2 ± 1.3 9.0 ± 3.1 0.000 Crohns disease location Disease duration (years) 10.9 ± 8.0 16.7 ± 9.3 0.000 L1 ileal 37 (12.17) 26 (14.36) 0.487 Age (years) 40.2 ± 14.1 42.9 ± 14.4 0.031 L2 colonic 35 (11.51) 26 (14.36) 0.360 Sex (male) 138 (45.39) 103 (56.91) 0.015 L3 ileocolonic 67 (22.04) 53 (29.28) 0.074 Race L4 includes upper GI 17 (5.59) 13 (7.18) 0.482 Caucasian 208 (68.42) 144 (79.56) 0.008 Unknown 16 (5.26) 14 (7.73) 0.274 Black 18 (5.92) 5 (2.76) 0.199 Crohns disease behavior 0.014 Asian 23 (7.57) 9 (4.97) 0.345 B1 non-stricture/penetrate 62 (20.39) 55 (30.39) Other 48 (15.79) 16 (8.84) 0.037 B2 stricturing 24 (7.89) 17 (9.39) Hispanic 37 (12.17) 12 (6.63) 0.089 B3 penetrating 17 (5.59) 14 (7.73) Insurance 0.098 B4 stricture and penetrate 11 (6.58) 11 (9.26) Private 260 (85.81) 160 (88.40) Unknown 190 (62.50) 84 (46.41) Medicare 14 (4.62) 15 (8.29) Perianal disease 42 (13.82) 37 (20.44) 0.056 Medi-cal/Medicaid 15 (4.95) 4 (2.21) Ulcerative colitis location 0.912 Other 2 (0.66) 0 (0.00) E1 proctitis 3 (3.49) 1 (2.04) None 11 (3.63) 2 (1.10) E2 left-sided colitis 23 (26.74) 16 (32.65) Smoke 0.658 E3 extensive 47 (54.65) 25 (51.02) Current 13 (4.28) 7 (3.87) Unknown 186 (61.18) 133 (73.48) Former 49 (16.12) 35 (19.34) Extra-intestinal Manifestation Never 242 (79.61) 139 (76.80) Uveitis 10 (3.29) 5 (2.76) 0.746 Past medical history Oral ulcers 19 (6.25) 7 (3.87) 0.260 Other autoimmune 40 (13.16) 14 (7.73) 0.066 Peripheral arthropathy 41 (13.49) 16 (8.84) 0.124 Diabetes mellitus 12 (3.95) 3 (1.66) 0.159 Axial arthropathy 15 (4.93) 14 (7.73) 0.208 Cardiovascular disease 10 (3.29) 5 (2.76) 0.746 Inflammatory skin changes 11 (3.62) 5 (2.76) 0.610 Hypertension 17 (5.59) 14 (7.73) 0.351 Primary sclerosing cholangitis 7 (2.30) 2 (1.10) 0.345 1st degree FH of IBD 26 (8.55) 19 (10.50) 0.475 Prior IBD surgery Non 1st degree FH of IBD 23 (7.57) 10 (5.52) 0.388 SBR 13 (4.28) 14 (7.73) 0.108 IBD type 0.000 Colectomy 10 (3.29) 10 (5.52) 0.231 Crohns disease 155 (50.99) 120 (66.30) IPAA 5 (1.64) 3 (1.66) 0.992 Ulcerative colitis 139 (45.72) 56 (30.94) Ileostomy 6 (1.97) 3 (1.66) 0.803 Indeterminate 10 (3.29) 5 (2.76) Other 11 (3.62) 6 (3.31) 0.860 Categorical variables presented as n (%). Continous variables presented as mean ± standard deviation. TNFi = tumor necrosis factor inhibitor; FH = family history; IBD = inflammatory bowel disease; SBR = short bowel resection; IPAA = ileal pouch-anal anastomosis.